G protein-coupled receptors (GPCRs), which relay chemical signals such as hormones from outside to the inside of cells, are the targets of approximately a third of the medicines on the market today. However, many of the GPCR-acting medicines were discovered
decades or more ago, without today’s more detailed knowledge about and tools for working with GPCRs. The receptors span the membrane seven times, thus are challenging to solubilize and study in vitro. Recent biophysical advances though have
bypassed some of the membrane-embedded challenges and enabled GPCR structural insights and spurred new screening applications. The receptors’ signaling complexities due to their ability to couple to a variety of G proteins (biased signaling)
are also now more understood and capitalized upon to design more selective drugs. CHI’s well-established GPCR-Based Drug Discovery conference will continue to convene prominent scientists in both academics and industry to share and discuss the
latest advances in applied GPCR research ranging from new screening assays and biophysical techniques, to structure-based drug development to medicinal chemistry optimization case studies to examples of GPCR-targeted compounds in development.

2:55 Structural Pharmacology of GPCRs in Asthma and Structure-Based Drug Development

Cheng Zhang, PhD, Assistant Professor, Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine

We present a series of crystal structures of two chemoattractant GPCRs, the C5aR and the CRTH2, as new targets for anti-inflammatory drugs. The structures reveal the molecular basis for the action of their antagonists including two drug candidates
that are currently in the late-stage clinical trials for treating ANCA-associated vasculitis and asthma respectively, and provide new insights into drug development. Based on the structures, we have identified compounds with novel structural scaffolds
as potential antagonists of these two receptors, which may lead to new drugs with improved pharmacological properties.

Apelin receptor (APJ) plays important roles in a variety of physiological processes such as heart contractility, energy metabolism and fluid homeostatic. We will report APJ high resolution crystal structure and molecular mechanism of receptor activation
and signaling selectivity. These results shed light on the understanding of the general mechanism of class A receptor activation and functional selectivity, and will facilitate the rational design of novel therapeutics with improved pharmacokinetic
and pharmacodynamics properties.

Research of tomorrow is moving quickly toward a more collaborative, open source and platform-independent environment. CDD Vault (Assay Reg/ELN/Viz) now incorporates “BioAssay Express” that utilizes machine learning to scan and catalog
libraries of human-readable assay text into computer-readable format to better access private, collaborative and public assay data.

4:25 Refreshment Break in the Exhibit Hall with Poster Viewing

New GPCR-Targeted Assays And Compounds

5:00 Identification and Optimization of a CGRP Receptor Antagonist of Novel Chemotype

I describe our strategy to rapidly evolve a series of CGRP receptor antagonists utilizing physical property, ligand efficiency, and diversity-guided iterative library design as well as evidence that these molecules make novel interactions in the binding
site (from receptor mutagenesis, X-ray crystallography, and NMR data). I also discuss lead optimization efforts that led to an advanced candidate with high affinity for the receptor, potent in vivo activity, good off-target
selectivity, and a low potential human dose.

We recently demonstrated that a class of GPCRs promotes endosomal signaling by forming “megaplexes” composed of a single GPCR that interacts simultaneously with β-arrestin, which drives the receptor internalization, and G protein,
which initiates signaling from internalized compartments. Now we are applying a variety of electron microscopy (EM) and computational methods to obtain high-resolution structural information about the megaplex (cryo-EM), and to visualize GPCR
signaling on the endosomal surface within living cells.

Grab a cup of coffee and join a breakout discussion group. These are informal, moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future
collaborations around a focused topic. Details on the topics and moderators are available on the conference website.

The mu opioid receptor Oprm1 is a member of the G-protein coupled receptor family. First demonstrated in 1973, it led to the discovery of the endogenous opioids and the ‘sodium effect’ in which sodium ions allosterically transition receptors
between agonist and antagonist conformations – now established with most GPCRs. Cloning the receptor uncovered a vast array of Oprm1 splice variants, including an atypical target capable of eliciting analgesia without the side effects associated
with classical opioids.

Studies in Dr. Lakshmi Devi’s laboratory aim at unraveling the molecular mechanisms of signal transduction mediated by G-protein coupled receptors (GPCRs) and their regulation in health and disease. Recent studies have focused on the identification
of compounds targeting opioid receptor heteromers as well as ligands targeting recently deorphanized hypothalamic neuropeptide GPCRs. This presentation will focus on different approaches used in novel ligand identification for the treatment of
pain and addiction.

The angiotensin II type 1 receptor is a premier model system for studies of biased agonism in GPCRs, as it has both Gq-biased and β-arrestin-biased agonists that have been exceptionally well characterized. Here we use multiple structural techniques
to elucidate the distinct angiotensin receptor conformations stabilized by functionally diverse ligands. Our findings suggest mechanisms by which biased agonists induce the receptor to couple selectively to particular transducers and achieve their
different biological profiles.

10:05 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

Terry
Kenakin, PhD, Professor, Department of Pharmacology, University of North Carolina School of Medicine

I will compare the muscarinic receptor Gq protein activation profiles of five exemplar molecules (slow binding agonists, partial agonists, inverse agonists, PAM-Agonists and Beta-PAMs) in calcium and IP1 assays to illustrate how quantitative comparisons
to pharmacological models can both identify mechanisms of action and also convert descriptive findings to predict data for therapeutic systems. Using these models optimally allows the identification of consistent and simple scales of activity
that can guide medicinal chemistry.

The success rate of a candidate drug moving through the clinical development phase is disappointingly low despite the fact that properties of drug candidates for a given therapeutic target are mostly optimized with respect to standard pharmacological
parameters of affinity, potency and intrinsic activity. Determining drug target binding kinetics, next to traditional potency measures, may increase the rate of success. Our work provides new insights in ligand-GPCR interactions and underlines
the importance of measuring binding kinetics of both drug candidates and competing endogenous ligands.

We employed two screening strategies to identify antagonists at protease activated receptor (PAR2), one being a DNA-encoded library screen on PAR2 and the second a fragment screen using a stabilized PAR2 GPCR receptor. From these efforts, we identified
two lead series of compounds, each of which bind to distinct and previously unknown allosteric sites. These results illustrate the power of integrating stabilized GPCR technologies into established screening paradigms.

2:30 Synergizing Applications of Biophysical Methods for Better Lead Generation

Expressing, purifying and analysing membrane proteins using SPR is routinely challenging. In this presentation, we will present our latest results demonstrating a scalable method for the successful development of SPR assays for a wide range of wild-type
GPCRs. The SPR assays can be exploited for fragment screening and kinetic characterization to discover novel ligands.

We present a method for manufacturing membrane bilayer nanodiscs encircled by DNA scaffold or covalently circularized Apolipoprotein A1 variants. We are able to extend the size of nanodiscs up to 90 nm in diameter. Furthermore, we demonstrate the potential use of these nanodiscs as model membranes to study virus entry. Finally, we demonstrate the potential use of these newly engineered nanodiscs in GPCR and antiviral drug discovery.